Pneumocystis carinii is an opportunistic pathogen that can cause lethal pneumonia in immunocompromised patients. The incidence of P. carinii pneumonia has continued to increase since the 1980s with the increase in the number of AIDS cases during this period. In spite of prophylactic treatment, AIDS patients often have recurrent P. carinii infections. The current standard therapies can also cause serious complications for AIDS patients. Clearly novel and improved therapies are required to deal with the worldwide burdens caused by P. carinii infections. A powerful multi- disciplinary scientific approach involving the fields of Molecular Biology, Chemistry and Drug Discovery is being pursued to identify lead compounds that can selectively inhibit the function of essential P. carinii aminoacyl-tRNA synthetase enzymes. Significant divergence of the structures of tRNA synthetase enzymes between species makes it feasible to identify novel and specific drugs with low toxicity. The target synthetases will be produced and characterized. A high-throughput, cost effective screening program will be implemented to identify inhibitor molecules. A diversity of compounds will be chemically synthesized and lead molecules will be optimized. Ultimately our advances will lead to the commercial sale of anti-microbial agents to treat P. carinii and perhaps other infectious diseases. PROPOSED COMMERCIAL APPLICATION: Technical innovative advances will be made in the: 1) Identification of novel P. carinii targets for antimicrobial therapy; 2) Development and use of novel, automated high- throughput screening assays; 3) Synthesis of classes of novel small molecules made by combinatorial chemistry techniques and classical medicinal chemistry; 4) Identification of novel small molecules with anti- microbial activity. Ultimately, these innovative advances will lead to the commercial sale of anti-microbial agents to treat P. carinii and other infectious diseases.